This multidisciplinary research program project is focused on chronic rejection of heart transplants. Although advances in immune suppression and improvements in the diagnosis and treatment of acute rejection and infection have improved the survival for heart transplant recipients the first year, long-term survival is limited by chronic rejection. The lesion that ultimately causes chronic rejection is accelerated graft arteriosclerosis (AGA). The only treatment currently available for AGA is retransplantation, but retransplantation entails increased patient risk, and it exacerbates the increasing shortage of donor hearts. Although the gross and microscopic features of AGA have been well characterized, the cellular and molecular mechanisms leading to AGA need to be determined. It is clear that AGA is a complex and multifactorial process. This program project focuses antigen-independent and antigen-dependent responses that causes of vascular injury leading to AGA. The 3 projects will investigate the following interactive mechanisms of vascular injury and response to injury: 1) complement and antibody-mediated injury; 2) regulation of Weibel-Palade body secretion by endothelial cells; and 3) granzyme B-induced proteolysis of smooth muscle cell targets. We hypothesize that these mechanisms occur in the initial phases of AGA and represent potential novel targets for intervention before AGA is irreversible. Each of the 3 projects makes use of the extensive clinical material from human cardiac transplant recipients in the Clinical/Pathology Core to verify experimental data from animal models developed in the Animal Core.